This phase II, randomized, blinded study will evaluate the potential of high doses of rifampin (RIF) to shorten treatment for tuberculosis (TB) in Peru and Brazil. RIF is the only first-line anti-TB drug for which in vitro, animal, &human evidence all support the idea that higher daily doses will increase plasma concentration &antimicrobial activity, but not toxicity. The primary study aims are to assess the following among 3 study arms (oral doses of RIF 10, 15 &20 mg/kg/day) during the initial 8 weeks of daily 4-drug treatment: 1) the difference in steady state pharmacokinetic (PK) exposure of RIF &25-desacetyl-rifampin;2) the difference in bactericidal action on persisting bacilli (sterilizing activity);3) the frequency of adverse events. Patients with smear-positive, newly diagnosed, drug-susceptible TB who consent to participate will be randomly allocated to 3 weight-based doses of RIF &standard doses of 3 companion drugs for 2 months of daily, supervised therapy. AUC/MIC, which will be assessed after 14 days of RIF dosing, is the PD parameter most closely linked to RIF activity against M.tb in pre-clinical studies. Sterilizing activity, the most important predictor of the potential to decrease treatment duration without increasing failure &relapse, will be assessed through 4 bacteriologic measures. This study would be first in humans to characterize the relationship between AUC/MIC &sterilization for anti-TB drugs. Correlation would provide proof of the shortening concept with high doses of RIF. Evaluation of adverse event frequency will generate evidence about toxicity risks conferred by increased doses. Substudies will examine lipid-body content of organisms in sputum as a potential surrogate marker and frequency &impact of mixed strain infections detectable in pooled sputum. This work advances one of the NIAID areas of investigation, "research to develop new &improved diagnostics, treatments, &vaccines" for emerging &re-emerging diseases. This project also addresses Specific Activity 2.4 of the NIAID MDR/XDR TB Research Agenda to "investigate optimal use of first &second line regimens to shorten the time patients remain infectious &contribute to M. tuberculosis transmission..." More active, shorter treatment could reduce the emergence of drug-resistant strains. PUBLIC HEALTH RELEVANCE: This study aims to develop improved treatment for the 9 million people who become sick with TB globally each year. Shortened treatment, especially with an inexpensive, widely available drug may increase access to treatment by reducing both the treatment burden on health-care workers &the probability of treatment default. Higher doses may increase probability of cure, which occurs in <80% of patients treated globally.